PROJECT SUMMARY Most adults in the United States have consumed alcohol at least once. Within that population, however, only 10-15% develop alcohol use disorder (AUD), indicating that majority may be intrinsically protected against alcohol addiction. Brain-derived neurotrophic factor (BDNF) signaling via the tyrosine-receptor kinase B (TrkB) receptor plays a role in preventing the escalation of alcohol intake to excessive levels. The goal of this study is to establish the mechanisms and neural circuitry by which BDNF gates alcohol drinking. BDNF- expressing neuronal projections from the orbitofrontal cortex (OFC) to the dorsal striatum (DS) have been shown previously by the Ron laboratory to gate alcohol consumption in mice. The OFC is involved in updating and ranking reward values and the DS is necessary for the development of habitual or goal-directed action- selection strategies. I recently found that that systemic administration of a TrkB agonist reverts habitual alcohol seeking toward more goal-directed behavior in mice. I therefore hypothesize that the role of BDNF signaling in the DS, and specifically in OFC-DS circuitry, is to bias behavior away from habitual alcohol seeking and toward more goal-directed alcohol seeking and alternative rewards. Using innovative molecular, pharmacologic and behavioral approaches, I will test the following aims: Aim 1 will investigate the role of BDNF-expressing neurons in the OFC in promoting goal-directed alcohol seeking. I will train transgenic mice expressing Cre-recombinase in BDNF-expressing neurons to habitually self-administer alcohol. I will then use a chemogenetic strategy to specifically activate BDNF- expressing neurons in the OFC to determine whether BDNF-positive OFC neuronal activity is sufficient to shift mice from habitual to goal-directed alcohol seeking. Aim 2 will examine the role of BDNF signaling in the DS and in the OFC-DS circuit in habitual alcohol seeking. I will utilize pharmacological tools and circuit-specific genetic interventions to activate or inhibit BDNF signaling in the DS and in OFC-DS circuits and determine the effects these manipulations have on habitual versus goal-directed alcohol seeking action-selection strategies in mice. Aim 3 will establish the effects of BDNF signaling in the OFC-DS projection on ?preference-switching? between alcohol intake and social interaction. To test this hypothesis, I will use novel behavioral assays to assess differences in alcohol- and social interaction-seeking behaviors accompanied with pharmacological and circuit-specific genetic manipulations to alter endogenous corticostriatal BDNF signaling. If successful, this work will provide insight into the mechanism by which BDNF signaling keeps alcohol drinking in moderation and provide potential targets for future therapeutic interventions for AUD treatment.